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Editorial

A Policy of Preemption: The Timing of Renal Replacement Therapy in AKI

F. Perry Wilson

Clin J Am Soc Nephrol 9: 1510 1512, 2014. doi: 10.2215/CJN.07210714

Beliefs about when to initiate dialysis in patients with AKI are passionately held by nephrologists, and are on the whole unsupported by reliable evidence. In- deed, it may be the very lack of high-quality evidence that gives rise to such impassioned belief systems. It is commendable that the nephrology community has rec- ognized that addressing this lack of evidence should be a major target of research (1). Unfortunately, this research effort has been hindered by a lack of consen- sus on exactly what the timing issue is. Two main issues hamper research in this area. The rst is the tendency for researchers to cast the clinical question in the context of early versus late dialysis. This thinking inaccurately parallels efforts to de ne the appropriate initiation of dialysis in the CKD popula- tion. In advanced CKD, there is a sense (though it may be misplaced) of the inevitability of dialysis. In that setting, the question of whether to start early, perhaps with an eGFR . 10 but , 15 ml/min per 1.73 m 2 , versus later, has intuitive appeal (2). In AKI, however, dialysis may not be inevitable. Indeed, a recent study of post cardiac surgery patients revealed that of those who achieve AKI Network stage 1, only 12% progressed to a higher stage, and of those only 33% went on to receive dialysis (3). Thus, the decision to not initiate dialysis does not merely put off the therapy for some period of time; it may obviate the therapy entirely. Any study that attempts to address the timing question must therefore vociferously acknowledge that patients who do not receive dialysis early may recover, or die, without ever receiving dialysis late. The second major issue is a lack of consensus over what the de nition of earlyis. Studies using RIFLE, AKI Network, or Kidney Disease Improving Global Out- comes AKI severity scores have, in general, favored initiation of RRT in the lower stages (4,5). Studies ex- amining time from intensive care unit (ICU) admission are more varied but seem to suggest a bene t to initi- ation earlier in the ICU course (6 8). Data from the Pro- gram to Improve Care in Acute Renal Disease study suggests that outcomes of RRT are superior when the therapy is initiated at a lower BUN (9), although other cohorts have not found a similar relationship (10). Per- haps revealing the critical nature of the de nition of early, an analysis of the Beginning and Ending Sup- portive Therapy for the Kidney study revealed that patients who received RRT earlier relative to ICU

1510 Copyright © 2014 by the American Society of Nephrology

admission fared better than those who received RRT later. However, when this same population was strat- i ed along the median creatinine at initiation, those initiated at a higher creatinine had improved out- comes. Strati cation by BUN had no effect (11). In this issue of CJASN , Vaara et al. (12) shed light on the timing question by de ning a set of classic indica- tions for RRT in AKI, including hyperkalemia, acido- sis, and volume overload. Using data from the FINNAKI study (13), a prospective, multicenter ICU cohort study in which 33.7% of 2901 patients devel- oped AKI, the authors identify four groups of individ- uals: those who received RRT within 12 hours of developing conventional in dications, those who re- ceived RRT . 12 hours after developing conventional indications, those who received RRT before conven- tional indications, and a propensity-matched group of individuals who never received RRT. In terms of 90-day mortality, pre-emptive RRT appeared to be the most effective treatment strategy (the mortality rate was 26.9% compared with 48.5% among those who received RRT for conventional indications). Prior studies have been limited by the absence of a control group. As mentioned earlier, the salient ques- tion is not whether dialysis should be initiated early or late but rather early or not early. This requires the identi cation of a group of individuals who could rea- sonably receive dialysis, but didn t: a tall order for any observational cohort. In the absence of an adequate control, we must constantly wonder if the earlygroup, by whatever de nition, actually needed dialysis at all. Indeed, if we imagine a world in which all hospital- ized patients receive dialysis on admission, we would expect outcomes to be much better than the current state of affairs where only the most ill patients receive the therapy. Vaara et al. use a propensity score based matching strategy to overcome this limitation, a technique em- ployed by a few other groups, including our own (14,15). While we did not nd a bene t to early initia- tion of dialysis (rather, we found that dialysis was pref- erable to no dialysis when initiated among those with higher serum creatinine concentrations), we did not use the same de nition of early. In the current manuscript, the classic indications de ned by Vaara et al. are appealing in their breadth, but they may not translate easily into clinical practice.

Yale University School of Medicine, New Haven, Connecticut

Correspondence:

Dr. F. Perry Wilson, Yale University School of Medicine, 60 Temple St, 6th Floor, Suite 6C, New Haven, CT 06510. Email: Francis. p.wilson@yale.edu

www.cjasn.org Vol 9 September, 2014

Clin J Am Soc Nephrol 9: 1510–1512, September, 2014

Indeed, when confronted with a patient with AKI, classic indications may already exist (the median time from ICU admission to RRT indication was 0.5 hours). If we are lucky enough to nd a patient with AKI and no classic indications, we would be forced to base our dialysis decision on whether we believe this patient might have similar properties to those that were used to create the propensity-matched cohort. Vaara et al. do not imply, of course, that all ICU patients with AKI should be dialyzed, nor do they identify specic factors (outside of classic indications) that may be reasonable indica- tions. Moving forward, though, we must improve our ability to choose who should receive this therapy. A randomized trial is an appealing solution to this prob- lem, and several attempts have been made; however, these were underpowered to detect clinically relevant outcomes (16 18). There exist two active trials of dialysis timing in AKI. The Standard versus Accelerated Initiation of RRT in AKI (STARRT-AKI) trial has enrolled 100 critically ill pa- tients with a doubling of serum creatinine and oliguria or an elevated plasma neutrophil gelatinase associate lipocalin level at 12 centers across Canada (19). Participants were randomly assigned to receive RRT within 12 hours of ful- lling criteria or to usual care. While the primary outcome was protocol adherence, the study will also examine 90-day mortality in both groups. The Initiation of Dialysis Early Versus Delayed in the Intens ive Care Unit (IDEAL-ICU) study plans to enroll 864 patients with septic shock meeting RIFLE stage F across 24 ICUs in France (20). Patients will be randomly assigned to receive RRT within 12 hours of meet- ing eligibility criteria or to RRT 48 60 hours later. Although the investigators have operationalized a de nition of renal recovery that will allow patients randomly assigned to the delay group to avoid the treatment, the clear preference is that dialysis be performed in most trial participants. These trials may nally shed light on the bedeviling tim- ing question, but they are rea lly only a beginning. STARRT- AKI, while novel in its use of a biomarker as a potential inclusion criteria, is underpowered to detect signi cant out- come differences in the two groups, and (by enrolling in- dividuals with only a doubling of creatinine) may have a signi cant nondialysis rate in the control group. Conver- sely, the IDEAL-ICU study seems to demand that all patients receive some type of RRT, which may not follow clinical practice in which a watchful waitingapproach is commonly used (21). When the decision to start RRT is ambiguous, I am often asked why not.Indeed, the overarching trend over time seems to be toward earlier and more continuous dialysis (22). This question speaks to a misunderstood risk-benet cal- culus. Like all clinical decisions, the decision of whether to initiate dialysis depends on an appropriate assessment of the risks and benets of the therapy. But given the paucity of randomized trials of dialysis in AKI, we do not have reliable estimates of risk. Instead, we rely on a general intuition that the benet of RRT is (for some patients at least) obvious and the risk is minimal. It is possible that we are harming patients with RRT, through either the induction of hypotension or ex- posure to foreign materials such as catheters and the dialysis membrane itself (23,24). But these risks are often minimized when the discussion of dialysis initiation is breached. Its clear that this type of thinking will increase resource utilization and costs, especially in the critically ill (25).

Editorial: Timing of RRT in AKI, Wilson 1511

There seem to be three approaches available at this point:

( 1 ) Perform an extremely large clinical trial, adequately powered to detect outcomes of clinical import, such as mor- tality, and with enough patients to perform rational sub- group analyses employing va rious timing criteria; ( 2 ) perform multiple smaller clinical trials with extremely care- fully de ned inclusion criteria; and ( 3 ) reconsider our de - nition of AKI. Although they aren t ready for broad clinical use, biomarker panels may provide the best window into the physiology of AKI and are increasingly being studied (26 28). Beyond biomarker assays, simply improving pre- diction rules based on readily available clinical data may allow us to identify a population likely to progress, thus obviating the concern that early RRT will inevitably give treatment to those who might never require it. Full disclosure: I believe that prompt and prophylactic initiation of RRT is bene cial for certain patients. Unfortu- nately, I am not sure who those patients are. I remain con- cerned that the biased evidence favoring early RRT may be putting some patients in harm s way who would otherwise recover on their own.

Disclosures

None.

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Published online ahead of print. Publication date available at www. cjasn.org.

See related article, Timing of RRT Based on the Presence of Conventional Indications,on pages 1577 1585.